Catalysed olefin metathesis is one of the most flexible ways in which to make carbon-carbon bonds in general and double bonds (C═C) in particular (1, 2, 3). This reaction formally cleaves two different carbon-carbon double bonds (C═C) into four fragments that are recombined with two new C═C double bonds to form olefinic products in which the original fragment partners are exchanged. The last 10 years have seen an almost explosive increase in the use of this reaction for the production of fine chemicals, polymers and pharmaceuticals. The reaction is catalysed and the market for metathesis catalysts is reportedly worth $1.5 bn (12.5% of the total worldwide market for catalysts) and is expanding by 9-10% annually. The product of this transformation is in general a mixture of cis (Z) and trans (E) disubstituted isomers, with the thermodynamically more stable E-isomer usually being the major component. However, in certain instances the target product is either the pure E- or the pure Z-isomer.
For example, the biological, chemical and physical properties within a given pair of E- and Z-isomers may, in fact, be very different, highlighting the need for selective production of single isomers. The isomer mixtures produced have to be subjected to costly separation processes. Sometimes, the separation may be very challenging (4).
The catalyst is the main key to controlling the ratio with which the isomers are formed and the availability of robust and industrially compatible stereoselective catalysts is expected to expand the applicability of olefin metathesis in organic synthesis and polymerisation chemistry (3). Such catalysts would have a particular impact on the synthesis of large macrocycles by ring closing metathesis (RCM), strereoregular polymers (ROMP), and stereisomeric pure alkenes. The Z-alkene functionality is, in fact, required in many cases, either because it is present in the target molecule or because it is necessary for subsequent stereospecific transformations. A range of natural products with biological activity (e.g. anticancer, antibacterial, and antifungal) contain Z-alkene macrocyclic frameworks, see Table 1. In most of the cases, the cost of extraction of these molecules is prohibitive, and total synthesis is the only alternative (4, 5). The formation of such large rings is very challenging, with RCM standing out among the few alternative routes (1, 5, 6).
TABLE 1Representative examples of natural products to which synthetic accesscould be drastically simplified via cis-selective olefin metathesis.Natural productProperties and applicationNakadomarine AAnticancer, antifungal and antibacterialEpothilone A ($)Potent anticancerEpothilone C ($)Potent anticancerTurrianesAntineoplastic agentsMotuporamine CCytotoxic activity and/or anti-metaplasticactivity. Robust inhibitor of chick neuriteoutgrowthCruentaren AHighly cytotoxic F-ATPase inhibitorLatrunculin A ($)Actin-bindingLatrunculin B ($)Highly selective actin-bindingSophorolipid lactoneMicrobial biosurfactantEpilachnene ($)Antiinsectan activityCivetone ($)Musk odor for perfumesYuzu lactoneOlfactory moleculeAmbretolideOlfactory molecule($): commercial products
The stereochemical outcome is in general unpredictable and depends on many factors such as the nature of the substrate and of the catalyst, the reaction conditions and on the presence of specific additives (7-10). Time consuming and very costly empirical approaches are therefore required to improve the process of manufacturing the individual molecules. Hence, the quest for efficient stereoselective catalysts is to a large extent driven by commercial needs (3).
In recent years, several highly Z-selective catalysts have been discovered. The first examples were disclosed by Schrock and Hoveyda (cf., for example, catalyst A, FIG. 2) (11-14). These catalysts are based on molybdenum or tungsten and are capable of promoting metathesis transformations such as ring opening/cross metathesis (ROCM) (12), ring opening metathesis polymerisation (ROMP) (13), olefin homocoupling (14), cross-metathesis (CM) (15, 16), and RCM (17, 18).
More recently highly Z-selective ruthenium-based catalysts have been discovered. Grubbs and co-workers have developed Ru-catalysts involving a bidentate N-heterocyclic carbene (NHC)-adamantyl ligand. These catalysts have shown high selectivity in several processes: cross-metathesis (CM) (19), olefin homocoupling (20, 21), ring opening metathesis polymerisation (ROMP) (22, 23), ring closing metathesis (RCM) (24, 25), and ring opening/cross-metathesis (ROCM) (26). A different system, containing one 2,4,6-triphenylbenzenethiolate ligand has so far demonstrated high Z-selectivity in homocoupling reactions (27, 28). Finally, very recently Hoveyda and coworkers have developed another highly Z-selective system containing a dithiolate ligand (29), which has been applied in ring opening metathesis polymerisation (ROMP) and ring-opening/cross-metathesis (ROCM).
However, none of the Z-selective catalysts reported to date (i.e., neither those based on molybdenum or tungsten, nor those based on ruthenium) have demonstrated tolerance towards presence of air or acids during catalysis.
The present invention addresses the need for active and functional group tolerant stereoselective olefin metathesis catalysts by utilising anionic ligands of very different steric requirement. In olefin metathesis reactions, the thus obtained ruthenium and osmium catalysts selectively provide the thermodynamically less favoured Z-isomers. In addition to being Z-stereoselective, these catalysts display many of the attractive properties of commonly employed (i.e., non Z-selective) ruthenium-based catalysts for olefin metathesis. In particular, embodiments of the invention are highly active catalysts and demonstrate superior stability in air and under protic conditions. For example, in contrast to the other Z-selective catalysts, the systems of the present invention are able to affect Z-selective olefin metathesis in air using non-degassed (i.e., stored under air) olefinic substrates and solvents. Z-selective olefin metathesis can be carried out also in presence of a relatively strong acid (e.g. phenylphopshoric acid, one equivalent relative to catalyst). Moreover, they show tolerance towards a range of functional groups and solvents.